PROJECT SUMMARY: The oncologic success of checkpoint inhibition continues to dominate medical headlines. This therapy is designed to harness the body?s own immune system to eradicate cancer cells. However, multi-system immunogenic and pro-inflammatory adverse events (AEs) have been reported. The skeletal toxicities of immune therapy (IT) are unknown. Bone loss and occult fracture may be unrecognized sequelae of IT threatening long term cancer survival. Skeletal failure is associated with substantial morbidity and mortality but can be prevented; therefore, it is critical to understand the adverse effects of IT on bone metabolism and the mechanisms by which unfavorable remodeling states may occur. Preliminary data indicates that IT accelerates skeletal deterioration. As such, our central hypothesis is that 1) deliberate PD-1 blockade with consequent T-cell activation used for the treatment of malignancy has adverse downstream effects on bone health. Mechanistically, we hypothesize that 2a) systemic inflammatory and bone regulatory markers will change following checkpoint inhibition, and 2b) that these changes will be related to unfavorable alterations in skeletal metabolism. The long term goal of this research is to investigate skeletal AEs and mechanisms driving skeletal fragility in the face of checkpoint inhibition. Parameters of bone metabolism and health have not been examined in patients treated with IT. The objective of this proposal is to leverage resources of an existing, NIH-funded 40-week clinical trial investigating renal cell carcinoma (RCC) recurrence outcomes in post-nephrectomy patients treated with the PD1-inhibitor, nivolumab compared to observation alone. Serum bone turnover and inflammatory markers, bone mineral density, and reference point indentation (RPI) data will be measured in clinical trial participants to investigate the following specific aims: 1) To characterize the effect of nivolumab on measures of bone health including remodeling, density and material properties. We will follow patients enrolled in an approved, phase 3 randomized control trial of patients with RCC treated with of PD-1 inhibition (nivolumab). We will quantify baseline and post- treatment bone parameters to include the following: A) bone remodeling using serum bone turnover markers, B) bone density using dual energy X-ray absorptiometry, quantitative computed tomography, and C) bone material properties using reference point indentation; 2) To investigate inflammatory and immunogenic mechanisms by which T-cell activation with nivolumab administration mediates changes in parameters of bone remodeling, density and material properties. We will quantify baseline and post-treatment serum levels of A) circulating pro- and antiinflammatory cytokines, and B) circulating RANK-L and OPG. Serum findings will be correlated with changes in parameters of bone strength and metabolism. Bone loss can be prevented if at-risk groups on IT are identified and preemptively treated. Failure to consider skeletal survivorship could result in osteoporosis, fracture, disability and mortality despite patients emerging from treatment cancer-free.